Abstract Chronic kidney disease (CKD) is a major driver of mortality and a financial challenge for healthcare in the United States. Treatment options are scarce, indirect and not sufficient, whilst CKD is growing into one of the largest unmet medical needs of our time. Once the kidney is injured, progression of the disease is dependent on the degree of fibrosis, which can differ from patient to patient. We and others have made the unique observation that the soluble form of urokinase plasminogen activator receptor (uPAR) is a risk factor for incident and prevalent kidney diseases across the spectrum of CKD. suPAR is a three finger toxin that is produced by immature myeloid cells in the bone marrow and circulates in the plasma to regulate integrin function in the kidney. Elevated suPAR levels or the presence of certain suPAR isoforms are causally involved in CKD by mediating injury to both glomerular podocytes and proximal tubular cells through specific interactions with ? integrins. Building on our published and novel preliminary observations that suPAR-mediated integrin activation drives fibrotic programs in the kidney, we plan to investigate the consequences of suPAR interactions with distinct ? integrins in different nephron segments and explore its role in promoting both glomerular and tubulointerstitial fibrosis. Three independent aims are being proposed: First, we will determine the molecular mechanisms that translate suPAR-?v?3 integrin signaling into podocyte injuries and glomerular sclerosis using surface plasmon resonance assays, cultured cell experiments and suPAR transgenic mouse models. Second, we will determine the molecular mechanisms that drive suPAR-?v?6 integrin signaling in tubular injuries and tubulointerstitial fibrosis by genetically modifying the tubular integrin function. Third, we will investigate therapeutic modalities using peptide based blocking strategies for uPAR and its associated fibrotic pathways. Experiments outlined in this proposal will allow us to separate different steps in the suPAR cascade of kidney fibrosis and define best options to intervene. As such, insights from this grant will provide a basis for preventive and treatment strategies to combat suPAR mediated fibrosis and CKD.